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Journal articles

Pseudo-peptides Based on Methyl Cysteine or Methionine Inspired from Mets Motifs Found in the Copper Transporter Ctr1

Anne-Solene Jullien 1 Christelle Gateau 1 Colette Lebrun 1 Pascale Delangle 1 
1 RICC - Reconnaissance Ionique et Chimie de Coordination
SYMMES - SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé : DRF/INAC/SYMMES
Abstract : Most proteins involved in Cu homeostasis bind to intracellular Cu(I) in stable Cu(S-Cys)(x) environments, thanks to well-conserved cysteine-rich sequences. Similarly, the Cu(I) transport protein Ctr1, responsible for copper acquisition, binds Cu(I) in Cu(S-Met)(3) environments in conserved methionine-rich MXMXXM sequences, referred as Mets motifs. Pseudo-peptides based on a nitrilotriacetic acid scaffold and functionalized with three amino acids bearing thioether side chains, either methyl cysteine in T-1 or methionine in T-2, were synthesized as mimics of the Mets sequences found in Ctr1. These two ligands were obtained with good overall yields from commercial amino acids and demonstrate efficient chelating ability for Cu(I). Only one species, the mononuclear [CuT1,2](+) complex, was evidenced by electrospray ionizationmass spectroscopy (ESI-MS) and the circular dichroism signature obtained for the most constrained CuT1 complex having the shortest side chains showed reorganization of the pseudo-peptide scaffold upon Cu(I) complexation. Considering that thioether functions are neutral sulfur donors, the stability constants measured by competition with ferrozine are quite large: log K approximate to 10.2-10.3. The CuT1,(2) complexes are significantly more stable that those formed with linear peptides, mimicking isolated Mets motifs MXMXXM of the Cu transport protein Ctr1 (log K approximate to 5-6). This may be attributed to the preorganized pseudo-peptide scaffold, which arranges the three neutral sulfur donors toward the metal center. Such moderate affinity Cu(I) chelators are interesting for applications in chelation therapy, for instance, to induce minimum disturbance of Cu homeostasis in Wilsons disease treatments.
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Submitted on : Wednesday, March 14, 2018 - 11:54:48 AM
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Anne-Solene Jullien, Christelle Gateau, Colette Lebrun, Pascale Delangle. Pseudo-peptides Based on Methyl Cysteine or Methionine Inspired from Mets Motifs Found in the Copper Transporter Ctr1. Inorganic Chemistry, American Chemical Society, 2015, 54 (5), pp.2339-2344. ⟨10.1021/ic502962d⟩. ⟨cea-01731482⟩



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